Attenuation of vesicular stomatitis virus infection of brain using antiviral drugs and an adeno-associated virus-interferon vector

Wollmann, Guido; Paglino, Justin C.; Maloney, Patrick R.; Ahmadi, Sebastian A.; Pol, Anthony N. van den

doi:10.1016/j.virol.2014.10.035

Cited by 16 publications

(11 citation statements)

References 76 publications

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“…We also tested VSV-IFN-␤ (11). VSV-IFN-␤ shows an attenuated phenotype in vitro and in vivo outside the brain, although it can be lethal when injected directly into the mouse brain (50). In contrast to wild-type VSV, VSV-IFN-␤ was substantially attenuated when given by the intranasal route and evoked no adverse effect, consistent with an attenuated phenotype previously described (11,12), and safer than wild-type VSV.…”

Section: Resultssupporting

confidence: 80%

“…All four recombinants have been tested as possible vaccine vectors (38,(44)(45)(46)(47)(48)(49). Three additional recombinant VSVs were used for control purposes; all three have been previously used to test intracranial safety (18,41,50). They included a wild-type-like VSV-G/GFP, in which the green fluorescent protein (GFP) gene was expressed fused to a second copy of the VSV G gene (18,51); VSV-LCMV-GFP, which had the LCMV glycoprotein substituted for the VSV glycoprotein (41); and VSV-IFN-␤, which expressed mouse beta-interferon (11,21).…”

Section: Resultsmentioning

confidence: 99%

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Chikungunya, Influenza, Nipah, and Semliki Forest Chimeric Viruses with Vesicular Stomatitis Virus: Actions in the Brain

Pol

Mao

Chattopadhyay

et al. 2017

J Virol

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Recombinant vesicular stomatitis virus (VSV)-based chimeric viruses that include genes from other viruses show promise as vaccines and oncolytic viruses. However, the critical safety concern is the neurotropic nature conveyed by the VSV glycoprotein. VSVs that include the VSV glycoprotein (G) gene, even in most recombinant attenuated strains, can still show substantial adverse or lethal actions in the brain. Here, we test 4 chimeric viruses in the brain, including those in which glycoprotein genes from Nipah, chikungunya (CHIKV), and influenza H5N1 viruses were substituted for the VSV glycoprotein gene. We also test a virus-like vesicle (VLV) in which the VSV glycoprotein gene is expressed from a replicon encoding the nonstructural proteins of Semliki Forest virus. VSVΔG-CHIKV, VSVΔG-H5N1, and VLV were all safe in the adult mouse brain, as were VSVΔG viruses expressing either the Nipah F or G glycoprotein. In contrast, a complementing pair of VSVΔG viruses expressing Nipah G and F glycoproteins were lethal within the brain within a surprisingly short time frame of 2 days. Intranasal inoculation in postnatal day 14 mice with VSVΔG-CHIKV or VLV evoked no adverse response, whereas VSVΔG-H5N1 by this route was lethal in most mice. A key immune mechanism underlying the safety of VSVΔG-CHIKV, VSVΔG-H5N1, and VLV in the adult brain was the type I interferon response; all three viruses were lethal in the brains of adult mice lacking the interferon receptor, suggesting that the viruses can infect and replicate and spread in brain cells if not blocked by interferon-stimulated genes within the brain. IMPORTANCE Vesicular stomatitis virus (VSV) shows considerable promise both as a vaccine vector and as an oncolytic virus. The greatest limitation of VSV is that it is highly neurotropic and can be lethal within the brain. The neurotropism can be mostly attributed to the VSV G glycoprotein. Here, we test 4 chimeric viruses of VSV with glycoprotein genes from Nipah, chikungunya, and influenza viruses and nonstructural genes from Semliki Forest virus. Two of the four, VSVΔG-CHIKV and VLV, show substantially attenuated neurotropism and were safe in the healthy adult mouse brain. VSVΔG-H5N1 was safe in the adult brain but lethal in the younger brain. VSVΔG Nipah FϩG was even more neurotropic than wild-type VSV, evoking a rapid lethal response in the adult brain. These results suggest that while chimeric VSVs show promise, each must be tested with both intranasal and intracranial administration to ensure the absence of lethal neurotropism.

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Section: Resultssupporting

confidence: 80%

Section: Resultsmentioning

confidence: 99%

Chikungunya, Influenza, Nipah, and Semliki Forest Chimeric Viruses with Vesicular Stomatitis Virus: Actions in the Brain

Pol

Mao

Chattopadhyay

et al. 2017

J Virol

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“…The most problematic aspect of using VSV either as an oncolytic virus or as a vaccine vector against more dangerous viruses, including Ebola virus (34), HIV, and other pathogenic viruses, has been the concern about adverse effects of the virus within the brain (42,52). VSV neurotoxicity can be reduced by generating peripheral immunity in advance of intracerebral inoculation (42) or by administering exogenous type I interferon or via intracerebral viral vectors that generate interferon (53). Attenuated VSVs have been constructed by a number of molecular alterations, including reduction of cytoplasmic amino acids in the G protein, mutations in the M gene, particularly at M51, and adding genes upstream of viral genes to reduce the expression of viral genes (11,14,16,17), but most of these resultant VSVs still retain negative side effects in the brain due to neuronal infection leading to neuron death.…”

Section: Discussionmentioning

confidence: 99%

Lassa-Vesicular Stomatitis Chimeric Virus Safely Destroys Brain Tumors

Wollmann

Drokhlyansky

Davis

et al. 2015

J Virol

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High-grade tumors in the brain are among the deadliest of cancers. Here, we took a promising oncolytic virus, vesicular stomatitis virus (VSV), and tested the hypothesis that the neurotoxicity associated with the virus could be eliminated without blocking its oncolytic potential in the brain by replacing the neurotropic VSV glycoprotein with the glycoprotein from one of five different viruses, including Ebola virus, Marburg virus, lymphocytic choriomeningitis virus (LCMV), rabies virus, and Lassa virus. Based on in vitro infections of normal and tumor cells, we selected two viruses to test in vivo. Wild-type VSV was lethal when injected directly into the brain. In contrast, a novel chimeric virus (VSV-LASV-GPC) containing genes from both the Lassa virus glycoprotein precursor (GPC) and VSV showed no adverse actions within or outside the brain and targeted and completely destroyed brain cancer, including high-grade glioblastoma and melanoma, even in metastatic cancer models. When mice had two brain tumors, intratumoral VSV-LASV-GPC injection in one tumor (glioma or melanoma) led to complete tumor destruction; importantly, the virus moved contralaterally within the brain to selectively infect the second noninjected tumor. A chimeric virus combining VSV genes with the gene coding for the Ebola virus glycoprotein was safe in the brain and also selectively targeted brain tumors but was substantially less effective in destroying brain tumors and prolonging survival of tumor-bearing mice. A tropism for multiple cancer types combined with an exquisite tumor specificity opens a new door to widespread application of VSV-LASV-GPC as a safe and efficacious oncolytic chimeric virus within the brain. IMPORTANCE Many viruses have been tested for their ability to target and kill cancer cells. Vesicular stomatitis virus (VSV) has shown substantial promise, but a key problem is that if it enters the brain, it can generate adverse neurologic consequences, including death.We tested a series of chimeric viruses containing genes coding for VSV, together with a gene coding for the glycoprotein from other viruses, including Ebola virus, Lassa virus, LCMV, rabies virus, and Marburg virus, which was substituted for the VSV glycoprotein gene. Ebola and Lassa chimeric viruses were safe in the brain and targeted brain tumors. Lassa-VSV was particularly effective, showed no adverse side effects even when injected directly into the brain, and targeted and destroyed two different types of deadly brain cancer, including glioblastoma and melanoma. P atients diagnosed with high-grade gliomas in the brain have a poor prognosis and generally succumb to the tumor within a year (1, 2). Similarly, melanoma metastases in the brain also are a death sentence, with a similar or worse prognosis than glioma (3). Surgery, radiation, and chemotherapeutics can extend life modestly but often at the expense of quality of life. One approach to eliminating tumors is with oncolytic viruses, viruses that target and either destroy the tumor directly or genera...

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“…In vivo, AAV-mIFNb was the most effective by inhibiting VSV-CT9-M51 neurotoxicity in immunocompetent mice and increasing survival in VSV-CT9-M51 treated human glioblastoma-bearing immunodeficient mice. The study was more focused on safety, however some surviving mice showed complete tumour regression [56]. VSV has also been combined with NSC74859 (S3I-201), a specific inhibitor of STAT3 [57].…”

Section: Other Approaches To Improve Vsv Oncoselectivitymentioning

confidence: 99%

Recent advances in vesicular stomatitis virus-based oncolytic virotherapy: a 5-year update

Felt

Grdzelishvili

2017

Journal of General Virology

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Oncolytic virus (OV) therapy is an anti-cancer approach that uses viruses that preferentially infect, replicate in and kill cancer cells. Vesicular stomatitis virus (VSV, a rhabdovirus) is an OV that is currently being tested in the USA in several phase I clinical trials against different malignancies. Several factors make VSV a promising OV: lack of pre-existing human immunity against VSV, a small and easy to manipulate genome, cytoplasmic replication without risk of host cell transformation, independence of cell cycle and rapid growth to high titres in a broad range of cell lines facilitating large-scale virus production. While significant advances have been made in VSV-based OV therapy, room for improvement remains. Here we review recent studies (published in the last 5 years) that address 'old' and 'new' challenges of VSV-based OV therapy. These studies focused on improving VSV safety, oncoselectivity and oncotoxicity; breaking resistance of some cancers to VSV; preventing premature clearance of VSV; and stimulating tumour-specific immunity. Many of these approaches were based on combining VSV with other therapeutics. This review also discusses another rhabdovirus closely related to VSV, Maraba virus, which is currently being tested in Canada in phase I/II clinical trials.

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Attenuation of vesicular stomatitis virus infection of brain using antiviral drugs and an adeno-associated virus-interferon vector

Cited by 16 publications

References 76 publications

Chikungunya, Influenza, Nipah, and Semliki Forest Chimeric Viruses with Vesicular Stomatitis Virus: Actions in the Brain

Chikungunya, Influenza, Nipah, and Semliki Forest Chimeric Viruses with Vesicular Stomatitis Virus: Actions in the Brain

Lassa-Vesicular Stomatitis Chimeric Virus Safely Destroys Brain Tumors

Recent advances in vesicular stomatitis virus-based oncolytic virotherapy: a 5-year update

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